Tumor necrosis factor alpha inhibits the hormonal response of the pituitary gland to hypothalamic releasing factors.

Tumor necrosis factor alpha (TNF alpha), a monokine produced by activated macrophages and monocytes, may be an essential mediator of the pathogenesis and of the hormonal response to endotoxic shock. It has been suggested that an elevated level of TNF alpha is a marker for morbidity and mortality during septic shock, and that treatment with antibodies against TNF alpha decreases mortality. Because monokines have been shown to interact at the hypothalamic-pituitary level, we have studied the effect of TNF alpha on basal and stimulated hormone release from normal rat anterior pituitary cells. After 3 days of incubation, primary cultures of rat anterior pituitary cells were stimulated with either 0.5 ng/ml CRF, 3 ng/ml AVP, 10 ng/ml angiotensin II (AII), 10(-6) M TRF, 10(-8) M LHRH, or 10(-8) M GHRH, alone or in the presence of 20 or 50 ng/ml human or murine recombinant TNF alpha. The culture media were analyzed for ACTH, GH, LH, and PRL content. Each experiment was performed in triplicate and was repeated 3 to 8 times. Time-course experiments (n = 3) demonstrated that TNF alpha inhibited CRF-stimulated ACTH production over a period of 8, 16, and 24 h, but had no effect before a period of 4 h. At doses ranging from 1 to 100 ng/ml, TNF alpha did not affect basal ACTH secretion but inhibited CRF-stimulated ACTH release in a dose-dependent manner (ED50 approximately 10 ng/ml). At a dose of 50 ng/ml, TNF alpha inhibited AVP-stimulated ACTH release by 30% and blocked the effect of AII. TNF alpha (20 and 50 ng/ml) completely prevented the CRF-AVP potentiation of ACTH release. Similarly, TNF alpha inhibited the stimulated release of GH (100% inhibition), LH (35% inhibition), and PRL (100% inhibition). TNF alpha had no effect on the basal secretion of GH or LH but inhibited basal PRL in a dose-dependent manner. The administration of the monokine did not cause any cellular damage because 48 h after removal of the TNF alpha treatment the cells showed normal basal and stimulated hormone levels in response to their specific stimuli. Incubation of TNF alpha solutions with antibody to TNF alpha reversed all TNF alpha actions. These data suggest that TNF alpha inhibits the secretion of pituitary hormones and particularly suppresses the response of the corticotroph cells. This inhibitory effect may contribute to the increased mortality observed in cases of severe septic shock with high circulating TNF alpha levels.